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Radiation therapy remains important in the modern management of both Hodgkin and non-Hodgkin lymphoma. Radiation is applied as both consolidation therapy post chemotherapy and primary therapy for selected limited volume clinically favorable histology. Application of modern therapy techniques permits more sparing of normal tissue in all anatomical locations. Modern image guidance permits both security in daily patient treatment set up and permits strategic titration of the planning target volume to further spare normal tissue. Four-dimensional planning makes certain targets are fully treated in all phases of the breathing cycle. Dose painting with altered fractionation permits identification of low, intermediate, and high-risk areas of concern and treat each in a single plan with multiple fractionation schemes saving both time of treatment and cost of therapy. In this paper we present multiple examples of the application of modern therapy techniques in lymphoma management and demonstrate advantages of modern radiation in several anatomical regions.

Mucous membrane plasmacytosis (MMP) is an uncommon variant of mucositis represented by a polyclonal plasma cell infiltration of mucosal tissue. Various clinical presentations in the upper airway have been reported ranging from erythematous mucosa to fungating masses. Histologic features include mucosal epithelial hyperplasia or psoriasiform changes with a dense submucosal infiltrate of polytypic plasma cells. Molecular studies for immunoglobulin gene rearrangement should be performed in all cases of MMP to rule out clonal neoplastic expansion of plasma cells. We present a case of MMP with over 15 years of clinical follow-up, emphasizing the relatively benign clinical course of this disorder.

Therapeutic leukapheresis can control the white blood cell count (WBC) of pregnant women with chronic myelogenous leukemia (CML) who have hyperleukocytosis without leukostasis. The medical justification for this treatment has not been objectively documented. We report a 27-year-old woman, diagnosed with CML at 10-week gestation, who developed severe dyspnea on exertion. A workup that included chest CT and echocardiography with a bubble study detected no cardiopulmonary pathology to explain her symptoms, and thus she was referred for leukapheresis. Prior to her first leukapheresis, which lowered her WBC from 154 × 10(3) /μL to 133 × 10(3) /μL, her oxygen saturation (SpO2 ) on room air decreased from 98 to 93% during 100 feet of slow ambulation and she was dyspneic. Just after the leukapheresis, her dyspnea on exertion was much improved and her SpO2 remained at 98% with repeat ambulation. Spirometry and lung volume studies obtained before and after her first leukapheresis demonstrated 32 and 31% improvements in forced vital capacity and forced expiratory volume in 1 s respectively, a 25% increase in functional residual capacity, and a 142% improvement in expiratory reserve volume. Residual volume decreased by almost 20%. Three times in a week, leukapheresis was continued until her WBC was controlled with interferon α-2b approximately 4 weeks later. Her dyspnea had completely resolved. She gave birth by elective caesarean section to a healthy boy at 32 weeks. Corroboration of symptom relief by leukapheresis with physiological data may justify such treatment in pregnant patients with CML. J. Clin. Apheresis 31:393-397, 2016. © 2015 Wiley Periodicals, Inc.

Summary.Objectiues. To evaluate haemophilia patients' knowledge and understanding of factor concentrate products and to assess their feelings regarding purity and viral safety of these products. Methods. Sixty questionnaires were distributed and completed by patients or parents of patients with severe/ moderate haemophilia A at two large comprehensive haemophilia centres in the USA and Italy. Results. Most patients knew what brand of factor concentrate they used, but less than half were aware of how their concentrate was virally inactivated. The majority of responders perceived recombinant factor VlII as being the concentrate with the highest degree of purity. The majority felt the decision of which concentrate to use should be the care-givers not the patients. Conclusions. It appears that patients need more education concerning the concentrate they are using, and its method of viral inactivation and purity.

Chronic basophilic leukemia is a rare and poorly characterized entity. Only a limited number of cases have been described. Herein, we report a patient who presented with fatigue, weight loss, leukocytosis, persistent prominent basophilia, and mild eosinophilia. The bone marrow showed features characteristic of a myeloproliferative neoplasm with a marked increase in maturing basophils. The basophils exhibited nuclear hypersegmentation, abnormal granulation, and abnormally low CD38 expression. Conventional karyotyping revealed a t(5;12)(q31;p13). ETV6 but not PDGFRB rearrangement was detected by fluorescence in situ hybridization.

ISTH07A1_P-T-118: Contact View [P-T-118] U.S. INHIBITOR PILOT PROJECT: STUDY DESIGN AND METHODS VALIDATION J.M. Soucie, C.H. Miller, M. Creary, W.C. Hooper, T.C. Abshire, D.B. Brettler, P. Bockenstedt, J. DiPaola, G. Massey, A. Neff, A. Shapiro, M. Tarantino, B.M. Wicklund, D. DiMichele, U.D.C. Working Group. Div of Blood Disorders, NCBDDD, Centers for Disease Control and Prevention; Dept. of Pediatrics, Emory University, Atlanta, GA; Dept. of Medicine, UMass Memorial Medical Center, Worcester, MA; Dept. of Internal Medicine, University of Michigan, Ann Arbor, MI; Dept. of Pediatrics, Univ. of Iowa Hospitals amp] Clinics, Iowa City, IA; Dept. of Pediatrics, Virginia Commonwealth Univ., Richmond, VA; Dept. of Medicine, Vanderbilt Univ., Nashville, TN; Hematology, Indiana Hemophilia and Thrombosis Center, Indianapolis, IN; Hematology, Comprehensive Bleeding Disorders Center, Peoria, IL; Dept. of Pediatrics, Children's Mercy Hospital, Kansas City, MO; Dept. of Pediatrics, Weill Medical College of Cornell Univ., New York, NY; Hemophilia Treatment Centers, Various Institutions, U.S., United States Introduction: The Universal Data Collection (UDC) Program of the Division of Blood Disorders at the Centers for Disease Control and Prevention (CDC) has initiated a pilot project at 9 U.S. Hemophilia Treatment Centers to perform post market surveillance for inhibitors. Goals are to prospectively collect risk factor and product exposure data, to provide centralized inhibitor monitoring, and to correlate inhibitor formation with genotype. Methods: Patients provide infusion logs with data on product brand, dose, and reason infused. A blood specimen is collected at baseline, annually, at product switch, or for clinical indication. Plasma and cells for DNA are shipped on cold packs to CDC, where inhibitor testing is done by the Nijmegen modification of the Bethesda assay, using commercially prepared buffered normal pooled plasma (BNPP) and deficient plasma from a hemophilic donor. A positive control with a known inhibitor titer is run with each assay. Specimens are screened for inhibitor at 3 parts patient plasma to 1 part BNPP. Positive specimens are retested in dilutions. Results are reported in Nijmegen-Bethesda units (NBU). The intron 22 inversion of the FVIII gene is detected using a modified version of longrange PCR. Utilizing the ABI 3730 Automated DNA sequencer, FVIII and FIX genes are sequenced in both directions, including both the 5' and 3' untranslated regions. Results: In the first year, 438 patients (80% hemophilia A) were enrolled. Comparison of 50 cold pack specimens to frozen specimens shipped on dry ice showed a correlation coefficient of 0.998. 406 inhibitor tests have been performed. The effects of infused FVIII or FIX and heat treatment of specimens are being investigated. More than 200 gene analyses have been done. Conclusions: Centralized monitoring of inhibitors is feasible and promotes quality control. Concurrent mutation analysis will add to the data on risk factors. International coordination of such data collection will produce a powerful tool for surveillance. Soucie JM, Miller CH, Creary M, Hooper WC, Abshire TC, Brettler DB, Bockenstedt P, DiPaola J, Massey G, Neff A, Shapiro A, Tarantino M, Wicklund BM, DiMichele D, U.D.C. Working Group. U.S. INHIBITOR PILOT PROJECT: STUDY DESIGN AND METHODS VALIDATION. J Thromb Haemost 2007; 5 Supplement 2: P-T-118 Date: Tuesday, July 10, 2007 file:////ddn-452/d/working/Rajan/Wileyml-3/2014/January/16-Jan/Tuesday/P-T-118.htm (1 of 2) [1/16/2014 8:20:24 PM] Abstract ISTH07A1_P-T-118: Contact ViewISTH07A1_P-T-118: Contact View Session Info: Poster: Haemophilia A and B Room: Exhibition Area file:////ddn-452/d/working/Rajan/Wileyml-3/2014/January/16-Jan/Tuesday/P-T-118.htm (2 of 2) [1/16/2014 8:20:24 PM]

Information from the medical records of 2650 US males with haemophilia living in six states was used to examine the influence of infusing factor concentrate at home (home therapy) and other variables on rates of hospitalization for a haemorrhagic bleeding complication (HBC) over a 4-year period. Bleeding complications included actual and suspected haemorrhagic events but excluded elective admissions for procedures necessitated by haemorrhage (e.g. joint synovectomy). Other risk determinants considered in the analyses included age, race, employment status, health insurance type, care received in federally funded haemophilia treatment centres (HTCs), factor deficiency type and severity, amount of factor prescribed, prophylactic treatment, and presence of inhibitors at baseline. Survival analysis methods were used to evaluate relationships between baseline risk factors and subsequent hospitalization rates. During 8708 person years (PYs) of follow-up, 808 subjects (30.5%) had a total of 1847 bleeding-related hospitalizations; an overall rate of 21.2 admissions per 100 PYs. Using proportional hazards regression to adjust for all of the studied factors, we found that home therapy use (among residents of four of the states) and care in HTCs were independently associated with a decreased risk for a first HBC. Patients who had government-sponsored health insurance or who had no insurance, those of minority race or ethnicity, those with higher levels of factor use, and those with inhibitors were at increased HBC risk. We conclude that the use of home therapy and receipt of care in HTCs are each associated with a substantially lower risk for HBC among males with haemophilia.

Inhibitors are a rare but serious complication of treatment of patients with haemophilia. Phase III clinical trials enrol too few patients to adequately assess new product inhibitor risk. This project explores the feasibility of using a public health surveillance system to conduct national surveillance for inhibitors. Staff at 17 U.S. haemophilia treatment centres (HTC) enrolled patients with haemophilia A and B into this prospective study. HTC staff provided detailed historic data on product use and inhibitors at baseline, and postenrolment patients provided monthly detailed infusion logs. A central laboratory performed inhibitor tests on blood specimens that were collected at baseline, annually, prior to any planned product switch or when clinically indicated. The central laboratory also performed genotyping of all enrolled patients. From January 2006 through June 2012, 1163 patients were enrolled and followed up for 3329 person-years. A total of 3048 inhibitor tests were performed and 23 new factor VIII inhibitors were identified, 61% of which were not clinically apparent. Infusion logs were submitted for 113,205 exposure days. Genotyping revealed 431 distinct mutations causing haemophilia, 151 of which had not previously been reported elsewhere in the world. This study provided critical information about the practical issues that must be addressed to successfully implement national inhibitor surveillance. Centralized testing with routine monitoring and confirmation of locally identified inhibitors will provide valid and representative data with which to evaluate inhibitor incidence and prevalence, monitor trends in occurrence rates and identify potential inhibitor outbreaks associated with products.

Summary. With the advent of new viral inactivation and purification methods for factor concentrates in the 1980s, transmission of both HIV-1 and hepatitis viruses has been significantly decreased. However, on routine annual testing of the paediatric population at the New England Hemophilia Center (NEHC), several children were noted to be hepatitis C (HCV) seropositive. Thus, a retrospective review of children with severe haemophilia was undertaken. Twenty-six children (median age: 7.5 years) under the age of 12 were identified. All were HIV-1 seronegative and had received hepatitis B immunization. Of these, 22 had received factor concentrate. Four children had no documented HCV serostatus, and seven were HCV seropositive using a second-generation ELISA. Transfusion products were reviewed and stored serum samples were evaluated using a second-generation ELISA to identify the approximate date of seroconversion with positive tests confirmed by RIBA analysis. Three children became seropositive before 1989 using factor concentrates with early viral attenuation procedures. Two children who seroconverted after 1991 received only monoclonal affinity purified factor concentrate that was either pasteurized or solvent/detergent treated. There was no evidence of horizontal or nosocomial viral transmission. We are unable to prove causality with the factor concentrates used by these children. Continued surveillance with sensitive measures for detection of HCV in persons with haemophilia using plasma-derived factor concentrate is necessary.

Background: Treatment of hemophilia patients with recombinant factor VIII concentrates has not previously been associated with anaphylaxis. Study Design and Methods: A 5-week-old boy with severe hemophilia A developed dyspnea, cyanosis, hypotension, and a diffuse urticarial rash following treatment with a recombinant factor VIII (Recombinate). To identify the cause of anaphylaxis in this patient, the vial lot was examined for the presence of endotoxin, and a checkerboard immunoblotting technique was used to test serum and/or plasma samples from the patient and mother for the presence of antibodies (IgA, IgG, IgE, and IgM) to Recombinate-related antigens (recombinant factor VIII, von Willebrand factor, human serum albumin, Chinese hamster ovary proteins, bovine serum albumin, mouse monoclonal anti-human factor VIII, polyethylene glycol 3350), and to ethylene oxide, the agent used to sterilize the infusion equipment. Results: No immune response directed against the Recombinate-related antigens or ethylene oxide that could be associated with the anaphylactic reaction was identified. Endotoxin was not present upon rabbit pyrogen testing of the therapeutic product. Conclusion: These studies failed to show any association between Recombinate and the onset of the allergic reaction. This seems to be the first reported case of anaphylaxis following the infusion of a recombinant form of factor VIII concentrate.

Summary There are numerous new coagulation factor concentrates that are being manufactured using recombinant technology. Some are available for use currently for the treatment of bleeding disorders and others are in clinical trials. Recombinant factor VIII concentrates are licenced in most countries and one FVIII concentrate with the B domain deleted should be available in the near future. Recombinant VIIa concentrate is in advanced phase III testing for the treatment of patients with inhibitor antibodies. Recombinant factor IX has been used successfully in animals and will be tested in humans shortly. This paper reviews these products and discusses their uses and possible side-effects.

Although disease develops within 10 years in most persons infected with human immunodeficiency virus type 1 (HIV-1), some remain symptom-free for prolonged periods.1,2 Most long-term asymptomatic survivors of HIV-1 infection still have evidence of disease progression in the form of declining CD4+ lymphocyte concentrations. However, some rare persons not only are asymptomatic but also maintain stable levels of CD4+ lymphocytes in the normal or near-normal range. Although the definition of nonprogression may vary, approximately 5 percent of seropositive persons have shown no HIV-related disease or declines in CD4+ cell counts despite 10 or more years of documented HIV-1 infection. . . .

A detailed, longitudinal study was undertaken to investigate the immunological and virological features of an individual with hemophilia infected with human immunodeficiency virus type-1 (HIV-1) for 10 years without disease. Methods applied to serial samples of peripheral blood included Western blot analysis, neutralizing antibody assays, antibody-dependent cell-mediated cytotoxicity (ADCC) titration, HIV-1 specific cytotoxic T lymphocyte (CTL) assays, viral cultures, and PCR with sequence analysis of viral regulatory genes. Strong antibody responses against HIV-1 antigens as measured by Western blot and ADCC assays have persisted throughout infection. Repeated attempts to isolate HIV-1 using sensitive culture techniques and to demonstrate viremia with standard PCR methods have failed. Using the "booster" PCR technique, a period of viremia in peripheral blood mononuclear cells was demonstrated. Concurrent with detection of circulating virus, titers of neutralizing antibodies and circulating HIV-1-specific CTLs became measurable. Sequencing studies of a portion of the viral genome showed no significant abnormalities of the regulatory genes. In this individual, the combination of low viral load in the peripheral blood and a strong, responsive immune system is associated with long-term, disease-free coexistence with HIV-1 infection.

Recent studies suggest that treatment of hemophiliacs with highly purified factor VIII concentrates may preserve immune function. To test this hypothesis, we prospectively studied 51 hemophilic patients (21 human immunodeficiency virus [HIV] seropositive and 30 seronegative) who were on home therapy exclusively with recombinant factor VIII (Kogenate, Miles Laboratory, Berkeley, CA) for 3.5 years. Patients, all of whom had been previously treated with plasma-derived factor VIII concentrates, were monitored every 6 months with T-lymphocyte subsets and beta 2-microglobulin levels. Mean rate of change in absolute CD4 cell counts, calculated from regression slopes for individual patients, showed a small but statistically significant decrease over the 3.5-year study period for HIV seropositive hemophiliacs. No decrease in CD4 cell counts was seen in HIV seronegative hemophiliacs when the data for children under age 6 years were excluded from the analysis. beta 2- microglobulin levels and CD8 cell counts remained unchanged. These data show stability of immunologic parameters in HIV seronegative hemophiliacs, and a small decrease in CD4 cell counts in HIV seropositive hemophiliacs treated with recombinant factor VIII.

The availability of monoclonal-antibody-purified factor VIII (FVIII) concentrates allows us to test the hypothesis, based on in vitro observations, that their use in HIV seropositive haemophiliacs would result in a difference in the rate of deterioration of immune function. We designed a multicentre, prospective, randomised, controlled study of symptom-free HIV-infected patients with haemophilia A who were assigned to receive either an intermediate-purity or monoclonal-antibody-purified product. All had CD4 lymphocyte counts of 100-600/microL, were negative for hepatitis B surface antigen, had not received any antiretroviral or immunomodulating drugs before study entry, and had previously received replacement therapy with intermediate purity FVIII concentrates. Use of antiretroviral therapy was permitted. 60 patients were recruited and 30 were assigned to each group. 35 completed the 3 year study, 20 in the monoclonal arm and 15 in the intermediate-purity arm. Among those completing the study, there were no differences between the two groups in the occurrence of AIDS-defining diagnoses (1 in each group). There were, however, striking and significant differences in terms of changes in absolute CD4 counts. The group receiving monoclonal-antibody-purified concentrates had essentially stable counts while a significant drop was observed in the group receiving intermediate-purity FVIII. These differences were independent of the use of antiretroviral therapy. These observations support the use of high-purity concentrates in the treatment of symptom-free HIV-positive patients with haemophilia A, and they should be taken into account along with cost, by doctors making therapeutic decisions.

A group of 58 heterosexual female partners (FP) of human immunodeficiency virus type 1 (HIV-1)-seropositive hemophiliacs was studied by conventional diagnostic methods such as enzyme-linked immunosorbent assay (ELISA) and Western blot analysis to examine whether any had acquired HIV-1 infection through sexual transmission. A subset of 29 FP were asked to answer a detailed questionnaire concerning their health, use of “safer sex” techniques, and other risk factors for HIV-1 infection. They also had additional blood drawn for CD4 cell analysis, viral cultures, nef, gag, and env immunoblots, and polymerase chain reaction (PCR) analysis to assess the occurrence of “silent” HIV-1 infection in a high-risk seronegative population. Among the 58 FP, three were found to be HIV-1-seropositive on first testing, with no new seroconversions occurring with subsequent testing in the remaining 55. Two seropositive FP had the additional testing and were found to have positive viral cultures, as well as positive PCR results. All of the seronegative FP (n = 24) who had additional testing were negative in viral culture, had negative immunoblots, and had no HIV-1 nucleic acid sequences detected by PCR. Thus, in this population, silent HIV-1 infection appears to be a rare occurrence and antibody testing seems to correlate with the more sensitive techniques of PCR and viral cultures.

To study the transmission rate of hepatitis C virus (HCV) in the female sexual partners of antibody-positive hemophilic males, 106 partners from three hemophilia centers located in Europe, America, and Australia were tested for HCV seropositivity using a first-generation enzyme- linked immunosorbent assay (ELISA-1) and, subsequently, a second- generation ELISA (ELISA-2) and a supplemental recombinant immunoblot assay. Additionally, the cohort was tested for the presence of antibody to the human immunodeficiency virus type-1 and hepatitis B virus markers. No female partner was HCV antibody-positive using the ELISA-1 test, whereas five were seropositive by the ELISA-2 test. Three of these five female partners were seropositive on the supplemental test, the remaining two having indeterminate results, for an overall prevalence of 2.7%. Thus, even with the use of sensitive testing, the prevalence of HCV infection remains low in this cohort, showing that the efficiency of heterosexual transmission of HCV is poor.

We have infused recombinant factor VIIa into patients with hereditary factor VII deficiency with marked reductions in plasma concentrations of factor IX activation peptide (FIXP), factor X activation peptide (FXP), and prothrombin activation fragment F1+2. These investigations show substantial elevations in these markers of coagulation activation and thereby demonstrate that the factor VII-tissue factor pathway is largely responsible for the activation of factor IX as well as factor X in the basal state (ie, the absence of thrombosis or provocative stimuli). We have administered a monoclonal antibody purified factor IX concentrate to individuals with hemophilia B. These studies show an increase in the plasma levels of FIXP that were initially greatly decreased, but no change in FXP or F1+2. We have also infused highly purified factor VIII concentrate into patients with hemophilia A. The data demonstrate no significant changes in the plasma concentrations of FXP and F1+2. The above observations indicate that factor IXa generated by the factor VII-tissue factor pathway is unable to activate factor X under basal conditions. Based upon the above findings, we outline a model of blood coagulation system function under basal conditions, and suggest a process by which the generation of factor Xa and thrombin might be accelerated during normal hemostasis and in the setting of thrombotic disorders.

A multicenter prospective study was carried out to evaluate whether a vapor-heated factor VIII concentrate transmitted blood-borne viral infections over a surveillance period of 15 months. Thirty-five patients with hemophilia and von Willebrand disease who had never received any blood components were treated. Twenty-eight were analyzed and found not to have non-A, non-B hepatitis. Sera from 20 of these 28 patients were also tested for the antibody to the hepatitis C virus. None had sero-converted during the follow-up period. None of the patients analyzed developed markers of the hepatitis B virus (n = 17) or the human immunodeficiency virus (n = 31). This vapor-heated factor VIII concentrate carries a low risk of transmitting hepatitis and human immunodeficiency virus infection.

The presence of cytotoxic T lymphocytes (CTL) to the gag antigens of human immunodeficiency virus (HIV) has been described in infected populations. We found that the majority of this immune response as measured in bulk CTL assays of unstimulated peripheral blood mononuclear cells (PBMC) is directed against the p24 component of the p55 gag precursor protein. Using limiting dilution analysis of this effector cell population we confirm that the majority of activated gag-specific CTL circulating in the PBMC of infected hemophilic patients are directed at p24 determinants and are present at frequencies of 1/36,000 to 1/86,000 lymphocytes. By performing in vitro stimulation after limiting dilution, the precursor population of gag-specific CTL are characterized and quantitated. HIV gag-specific CTL precursors are identified at frequencies of 1/1700 to 1/17,000 lymphocytes and are made up of cells with both p17 and p24 specificities. No HIV gag-specific CTL precursor cells are identified in the PBMC of HIV-uninfected individuals. These studies demonstrate that CTL directed at both p17 and p24 determinants make up the cellular immune repertoire in HIV-infected individuals but that only the p24-specific CTL are routinely found in an activated state in the circulation.

One hundred ninety-three asymptomatic patients with hereditary coagulation disorders and human immunodeficiency virus (HIV) infection were studied in a controlled trial of zidovudine (ZDV) versus a placebo (with an average of 9.7 months on study). Pretreatment characteristics were well balanced between the placebo and drug-treated groups, including CD4 distributions, types of clotting disorders, transaminase abnormalities, and use of various hemostatic agents. At the time of analysis, 161 patients either were still receiving treatment or had previously reached an endpoint of disease progression while receiving treatment. Twenty-five patients withdrew voluntarily. The toxic effects noted included granulocytopenia and anemia, especially in older patients, and subjective symptoms of asthenia, malaise, and nausea, consistent with the known consequences of treatment with 300 mg ZDV five times daily. There was a trend toward more diagnoses of acquired immunodeficiency syndrome (AIDS), advanced or early AIDS-related complex (ARC), single ARC symptoms, or death in placebo recipients as compared with those receiving ZDV (22 v 13). Because older patients with hemophilia have more rapid disease progression, the same efficacy analysis was performed in the 89 patients aged more than 30 years who were receiving treatment. In this subgroup, there was a similar trend (11 v 6). With regard to the most advanced problems of the infection among the older patients, there were five patients who were newly diagnosed with AIDS or died in the placebo group versus none in the ZDV group (P = .02) among the older patients. The pretreatment distribution of CD4 counts for the placebo and ZDV groups were similar, but patients aged more than 30 years had significantly (P less than .049) fewer CD4 cells than patients aged less than 30 years. A beneficial ZDV effect is also supported by a trend toward higher CD4 counts (a 48-cell increase in the ZDV group at 24 weeks as compared with a four-cell increase in the placebo group) and a significant (P = .03) difference in weight gain in the ZDV patients aged more than 30 years (8 pounds) as compared with the older placebo patients (aged more than 30 years) (2 pounds) at week 24. The findings in the asymptomatic hemophilic patients aged more than 30 years support a useful effect of ZDV, which is similar to observations in the larger study of its use in asymptomatic, nonhemophilic patients.

Cytotoxic T lymphocyte (CTL) responses to human immunodeficiency virus type 1 (HIV-1) gag proteins were studied prospectively in 17 children (12 infected) born of mothers with HIV-1 seropositivity and in five pediatric patients with hemophilia infected by transfusion of HIV-1-contaminated factor VIII concentrate. B lymphoblastoid cells infected with vaccinia virus vectors expressing HIV-1 gag gene products were combined with autologous peripheral blood mononuclear cells to detect circulating CTLs. Effector cells were defined by monoclonal antibody-mediated, complement-dependent cytolysis. Circulating HIV-1 gag-specific cytotoxic responses were detectable in 4 of 5 HIV-1-infected pediatric hemophilic patients, and were similar in magnitude to those previously described in adults. In contrast, circulating HIV-1 gag-specific cytolysis was detectible in only 3 of 12 vertically infected children. Depletion data revealed that the majority of detectible gag-specific cytolysis was CD8 T cell-mediated. No apparent relationships between CD4 T cell counts, CD8 T cells counts, or serum p24 antigen levels and CTL responses were seen. Deficient CTL development may, in part, explain the more rapid onset of symptomatic disease following vertical HIV infection.

A questionnaire-based survey involving 11,801 hemophiliacs from 54 hemophilia centers in the USA and Europe documented the occurrence of hepatocellular carcinoma (HCC) in 10 patients. The crude rate of HCC was 3.2/100,000 patients/year, at least 30 times higher than the background incidence of this tumor in the countries of origin of the patients. All patients were Caucasians with hemophilia A, 39 to 74 years of age, and had liver cirrhosis. All had one or more risk factor for cirrhosis and HCC: 5 were positive for serum hepatitis B surface antigen, 4 had the antibody to hepatitis C virus, and 4 had histories of alcohol abuse. Serum alpha-fetoprotein, measured in 6 patients, was significantly elevated in 4 (range: 807-1399 ng/ml), and only moderately elevated in 2 (25 and 171 ng/ml). The onset of HCC was asymptomatic in 5 patients, whereas it was accompanied by jaundice, abdominal pain, or ascites in the remaining patients. Thus, HCC seems to be a more important secondary disease for hemophiliacs than formerly recognized. Since HCC is often asymptomatic, screening hemophiliacs with chronic liver disease with periodic ultrasound scans might increase the changes of detecting HCC at a stage amenable to surgical treatment.

Background. Current treatment of hemophilia A, a hereditary disorder affecting approximately 1 in 10,000 males, relies on plasma-derived factor VIII concentrates. We tested the safety and efficacy of a recombinant factor VIII preparation for the treatment of this disorder. Methods. We conducted the investigation in three stages: comparing the pharmacokinetics of plasma-derived and recombinant factor VIII, assessing the efficacy of recombinant factor VIII for home therapy, and assessing its efficacy for major surgical procedures and hemorrhage. A total of 107 subjects with hemophilia, 20 of whom had not been treated previously, enrolled in the investigation. Results. The in vivo recovery and elimination half-lives of recombinant factor VIII equaled or exceeded those of plasma-derived factor VIII. Seventy-six subjects participated in a home-treatment program, using recombinant factor VIII for 69 to 807 days (median, 618); home diaries of 56 subjects treated for 5 months were analyzed. Of 540 bleedi...

V. Scleroderma in childhood. Arthritis Rheum 1977;20:34350. 3. Dilley J J, Perry HO. Bilateral linear scleroderma en coup de sabre. Arch Dermatol 1968;97:688-9. 4. Fitzpatrick TB, Eisen AZ, Wolff K, Freedberg IM, Austin KF. Dermatology in general medicine. 3rd ed. New York: McGraw-Hill, 1987:1842-3. 5. Fries R. Uber die hemiatrophia faciei. Klin Med (Wien) 1964;19:70-6. 6. Woo TY, Rasmussen JE. Juvenile linear scleroderma associated with serologic abnormalities. Arch Dermatol 1985; 121:1403-5. 7. Tuffanelli DL, Marmalzat WL, Dorsey CS. Linear scleroderma with facial hemiatrophy: report of three cases associated with collagen-vascular disease. Dermatologica 1966; 132:51-8. 8. Hanson V, Drexler E, and Kornreich H. Rheumatoid factor (anti-gamma-globulins) in children with focal scleroderma. Pediatrics 1974;53:945-7. 9. Falanga V, Medsger TA Jr, Reiclhin M. Antinuclear and anti-single-stranded DNA antibodies in morphea and generalized morphea. Arch Dermatol 1987;123:350-3. 10. Aver'ianov luN, Uvarova NN, Tskhovrebov TM, Maksimenko IM. Sindrom gemiatrofii litsa, ochagovoi sklerodermii i fokal'nykh epilepticheskikh pripadkov v sochetanii s dvustoronnim uveitom. Zh Nevropatol Psikhiatr (Rus) 1989;89:26-8. 11. Jablonska S, Rodnan GP. Localized forms of scleroderma. Clin Rheum Dis 1979;5:215-41. 12. Jablonska S. Scleroderma and pseudoscleroderma. 2nd ed. Warsaw: Polish Medical Publishers, 1975. 13. Rosenbaum JT, Nozik RA. Uveitis: many diseases, one diagnosis. Am J Med 1985;79:545-7. 14. Knox DL. Uveitis. Pediatr Clin North Am 1987;34:1467-85. 15. Wartenberg R. Progressive facial hemiatrophy. Arch Neurol Psychiatry 1945;54:75-96. 16. Simon HE, Kaye B. Progressive hemiatrophy of the face. Arch Neurol Psychiatry 1945;53:437-8. 17. Miller MT, Sloane H, Goldberg MF, Grisolano J, Frenkel M, Mafee MF. Progressive hemifacial atrophy (Parry-Romberg disease). J Pediatr Ophthalmol Strabismus t987;24:27-36.

Seven long-term nonprogressors (LTNPs) have been identified in a cohort of 128 human immunodeficiency virus (HIV)-1 infected individuals with hemophilia. Studies included quantitation of virus by polymerase chain reaction, characterization of primary virus isolates in vitro, analysis of lymphocyte surface markers, and measurement of virus-specific cytotoxic T lymphocytes (CTLs). Viruses of LTNPs exhibited slow growth in vivo and in vitro. LTNPs had expansion of CD8 T cells with increased expression of HLA-DR. Intermittent HIV-1-specific CTL effector activity was detected in freshly isolated peripheral blood mononuclear cells of most LTNPs. CTL precursor frequencies were higher in LTNPs than in patients with progressive disease. Virus antigen-specific lymphoproliferation was vigorous in some LTNPs. Thus, LTNPs in this cohort have maintained remarkably low virus burdens and vigorous HIV-1-specific cell-mediated immunity over a 15-year period. The presence of expanded, activated CD8 T cells with cytotoxic effector function in the peripheral blood suggests ongoing viral replication.

One hundred thirty-one patients followed at the New England Hemophilia Center (Worcester, MA) were tested for antibody to hepatitis C virus (HCV). All but two had used factor concentrate that had not undergone viral inactivation; two patients had used only cryoprecipitate. The overall prevalence of HCV antibody positivity was 76.3%. There was no significant difference in age or the amount of non-heat-treated factor concentrate used between the group that was HCV antibody positive and negative. There was also no significant difference between aminotransferase levels in the two groups. There was a positive association between HCV antibody and the presence of antibody to hepatitis B core antigen and antibody to human immunodeficiency virus. A group of 31 patients were tested twice for HCV antibody at intervals of 35 to 71 months. In this subset, 25 were repeatedly seropositive, 4 were repeatedly seronegative, and 2 went from seropositive to seronegative. These data confirm the previous impression that non-A, non-B hepatitis is a major sequela to the use of pooled coagulation factor concentrates. HCV infection may account for most of the chronic liver disease observed in this population. Anti-HCV testing of plasma donors and improved methods of viral inactivation should prevent new cases from developing.

The relationships between primary human immunodeficiency virus type 1 (HIV-1) Gag-specific cytotoxic T lymphocyte (CTL) frequency, virus load, and CD4 T cell loss were evaluated in a group of 46 HIV-1-infected persons with hemophilia. Freshly isolated peripheral blood mononuclear cells in limiting dilution assays were used to measure HIV-1 Gag-specific CTL frequencies. Concurrent measurements of virus load and lymphocyte surface markers were obtained. No correlation between Gag-specific CTL frequency and concurrent CD4 cell count was observed. A significant inverse relationship was observed between HIV-1 Gag-specific CTL frequency and provirus load as measured by polymerase chain reaction. Subjects with higher CTL frequencies were found to have more stable CD4 cell counts over time. These results provide additional evidence to support the concept that the predominant role of this virus-specific cellular immune response is to limit viral replication and CD4 cell loss in HIV-1 infection.

More than 600 U.S. hemophilia patients have been genotyped as part of the pilot study for a prospective surveillance system for factor inhibitors conducted at 12 U.S. Hemophilia Treatment Centers. 80% of enrolled subjects had hemophilia A, 58% with severe disease, 24% moderate, and 18% mild. Age ranged from This project is supported by the CDC Foundation through a grant from Wyeth Pharmaceuticals, which had no role in data analysis or abstract preparation.

Antibody to HTLV-I/II was detected in 19 (0.3%) of 6286 plasma donors from five regions of the United States (US). This seroprevalence rate is approximately 10 times that in whole blood donors. The regional distribution of infection was as follows: Southwest, 0.68 percent; Southeast, 0.45 percent; Midwest, 0.28 percent; Northwest, 0.1 percent; and Northeast, 0.0 percent. Rates of HTLV-I/II infection in blacks (0.74%) and Hispanics (0.66%) were higher (both, p less than 0.001) than those in whites (0.08%). All 19 infected units were donated by subjects aged 30 or older, even though 52.9 percent of the donations came from persons less than 30 years old. Equal rates of HTLV-I/II infection were found in men (0.31%) and women (0.29%). No HTLV-I/II antibody was detected in 154 French and 25 US hemophiliacs who were transfused regularly with noninactivated plasma or its derivatives. This suggests that the transfusion of HTLV-I/II-seropositive plasma products does not transmit the viral infection.

A pilot project of a prospective surveillance system for coagulation factors VIII and IX inhibitors has been initiated at 9 U.S. Hemophilia Treatment Centers (HTCs). More than 500 patients have been enrolled. Risk factor and product exposure data are recorded at each HTC. A blood specimen is collected upon entry, annually, at product switch, or for clinical indication and tested centrally at the CDC, using a modified Nijmegen-Bethesda method. Plasma from specimens collected in 4.5mL evacuated tubes containing 3.2% sodium citrate is shipped overnight on cold packs. Specimens are heated to 56oC for 30 minutes to remove endogenous and infused FVIII and centrifuged. Specimens are initially screened for inhibitor using a single dilution of 3 parts patient plasma to 1 part normal pool plasma buffered with imidazole to pH 7.4 (BNPP). Specimens showing inhibition and those from previously positive patients are tested in multiple dilutions at 1 part patient dilution to 1 part BNPP. Dilution is in naturally FVIII-deficient plasma containing normal von Willebrand factor. After a 2-hour incubation at 37oC, FVIII remaining in the patient mixture is divided by FVIII remaining in a 1:1 mixture of BNPP and FVIII-deficient plasma and expressed as % residual activity (RA). %RA is converted to Nijmegen-Bethesda units (NBU) using a curve with one NBU equal to 50% RA. An inhibitor plasma of known titer is run with each assay as positive control. Split specimens shipped frozen and on cold packs showed a correlation of 0.998. 3:1 and 1:1 mixtures showed a correlation of 0.97. Almost 50% of the first 200 specimens received had measurable FVIII activity. The heating step was introduced to remove FVIII without damaging the antibody. 65 specimens went from >100% RA to a titer of 0–0.2 NBU after heating. Among 538 specimens tested for FVIII inhibitors, 435 (81%) were from patients with no previous history of inhibitor (shown below). 429 (98.6%) were < 0.5 NBU. The 6 specimens (1.4%) with > 0.6 NBU are under investigation as possible seroconversions. Nijmegen-Bethesda Units in Patients with No Previous Inhibitor NBU No. Pts. (%) NBU No. Pts. (%) NBU No. Pts. (%) 0 220 (50.6%) 0.4 3 (0.7%) 0.8 1 (0.2%) 0.1 127 (29.2%) 0.5 0 0.9 0 0.2 59 (13.6%) 0.6 0 1.0–4.0 2 (0.5%) 0.3 20 (4.6%) 0.7 2 (0.5%) 5.0–19.0 1 (0.2%) Among 121 specimens tested for factor IX (FIX) inhibitors, 113 were from patients with no previous history of inhibitor and all had NBU

Inhibitors are now considered to be the most important complication of clotting factor replacement therapy in hemophilia. In January 2005, the Universal Data Collection (UDC) project, which includes data on over 14,000 patients with hemophilia A or B, was amended to include prospective data collection on inhibitors. We report interim results of a pilot project involving 9 selected Hemophilia Treatment Centers in the U.S. Dedicated data managers collected risk factor and product exposure data from enrolled patients on a monthly basis. Tracked infusion log submissions were used to estimate patient adherence to infusion log completion. A blood specimen is collected at baseline, annually, at product switch, or for clinical indication and is tested centrally for inhibitor using the Nijmegen modification method. Results are reported and any above a threshold value are followed up with repeat testing and clinical correlation. As of August 2007, 514 male patients with hemophilia, ages 2–84 years (mean 23 yrs SD 17) had been enrolled. Of these, 415 (81%) had FVIII deficiency (64% severe, 20% moderate, 16% mild) and 99 (19%) had FIX deficiency (35%, 43%, and 22%, respectively). 85% of the patients were caucasian, 8% black, and 4% Hispanic. A previous history of inhibitor was present at enrollment in 71 (14%). Prophylactic treatment was used by 37% and 80% received product by home infusion. Historical exposure to product collected at enrollment was as follows: 14% had 0–20 exposure days (ED), 12% had 21–100 ED, 7% had 101–150 ED, and 64% > 150 ED. During follow-up, 6 patients have had inhibitor titer measurements over 0.4 BU. One of these was known to have an active inhibitor at enrollment. Confirmatory testing of remaining cases is underway. Mean adherence rate for patient infusion log completion in the 9 HTC’s was 45% (range 7% to 74%). Overall adherence increased with time on study from about 40% at one month to nearly 60% for those enrolled at least 10 months. In summary, enrolled participants represent a wide range of characteristics including age, race, disease severity and number of factor exposures. Interim findings indicate that prospective collection of factor infusion data from hemophilia patients necessary to appropriately monitor inhibitor formation, is feasible but labor intensive and requires patient adherence to completion and submission of accurate infusion logs. Because inhibitor formation is rare and the potential risk factors are many, large scale studies with long-term follow-up will be needed to fully assess risk factors for inhibitors.

Over 80% of adults with hemophilia are infected with hepatitis C (HCV) infection through exposure to clotting factor concentrates 20 or more years ago. Although liver biopsy is considered the gold standard to assess the severity of HCV liver disease, the majority of those with hemophilia do not undergo biopsy, even by the less invasive transjugular route. Little is known about the actual or perceived bleeding risks which may affect patient decisions about biopsy. Further, little is known about the minimal hemostatic dose of factor replacement which may affect physician decisions about biopsy. Of 161 hemophilic men enrolled in the multicenter HIV and HCV in Hemophilia (HHH) study which evaluates extent of and risks for HCV disease progression, 112 (69.6%) have decided against biopsy. Among the reasons, given by 75 of the latter, were fear of the procedure, in 23 (30.7%); lack of insurance, in 11 (14.7%); past biopsy, in 11 (14.7%); lack of time, in 10 (13.3%); lack of perceived indication, in 6 (8.0%); presence of an inhibitor, in 5 (6.7%); fear of bleeding, in 5 (6.7%); and other illness or uncertainty, in 4 (5.3%). The 49 (30.4%) agreeing to liver biopsy were more likely than those declining biopsy to be HIV+ (53.1% vs. 34.8%, p < 0.05) and less likely to have an inhibitor (0% vs. 13.4%, p = 0.002), but were as likely to have hemophilia A, 81.6% vs. 83.0%; be over 35 years of age, 49.0% vs. 53.1%; Caucasian, 81.6% vs. 85.7%; and HCV genotype 1, 80.8% vs. 79.5%, all p > 0.05. At the time of biopsy, the median platelet count was 185,000/ul (38,000–366,000/ul), the median PT was 12.0 seconds (9.4–15.4 sec), and the median INR was 1.0 (0.9–1.2). All patients received two doses of factor, and 25 (71.4%) received a third dose; three (8.6%) received a fourth dose for unrelated procedures. The median pre- and post-biopsy F.VIII doses were 49.5 U/kg, 26.6 U/kg at 1–4 hours and 45.0 U/kg at 24–48 hours; and the median F.IX doses were 74.0 U/kg, 44.3 U/kg, and 45.0 U/kg, respectively. No biopsy-related bleeding occurred. Minor adverse events included fever in two, liver function abnormality in one, and duodenal ulcer bleeding in one. The median Knodell, Ishak, and Metavir scores did not differ significantly by HIV status (+ vs.), type hemophilia (A vs. B), age (>35 vs ≤ 35 yr), HCV genotype (1 vs. non-1), or race (Caucasian vs. non-Caucasian). Although preliminary, these findings suggest that fear of the procedure is the most common deterrent to liver biopsy in patients with hemophilia. Yet, when performed by the transjugular route, liver biopsy appears to be safe, with excellent hemostasis achieved with a minimum of two doses of factor, including a 100% dose pre- and a 50% dose post-biopsy. These findings will require confirmation in larger numbers of subjects.